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MDCT of Hypervascular Hepatocellular Carcinomas: A Prospective Study Using Contrast Materials with Different Iodine Concentrations

¹ Department of Radiology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
² Department of Radiology, Kinki University Nara Hospital, Nara 630-0293, Japan.

Received January 15, 2004; accepted after revision August 24, 2004.

 
Address correspondence to Y. Yagyu.

Abstract

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OBJECTIVE. The objective of our study was to investigate the effect of different iodine concentrations in contrast materials on the depiction of hypervascular hepatocellular carcinomas (HCCs) by MDCT.

SUBJECTS AND METHODS. This prospective study involved 100 consecutive patients with chronic liver disease, including 27 patients with hypervascular HCCs. The first 50 patients received 100 mL of iopamidol at a concentration of 370 mg I/mL (group A) and the subsequent 50, 100 mL at 300 mg I/mL (group B); in both groups, the contrast material was administered at a rate of 3.0 mL/sec. Unenhanced scanning and four-phase enhanced scanning at 25, 40, 60, and 180 sec after the start of contrast injection were performed. The enhancement of the aorta, liver, and portal vein was measured during each phase. In addition, tumor-to-liver contrast was calculated for the 27 patients with hypervascular HCCs. Of the 27 patients with hypervascular HCCs, 15 were in group A and 12 were in group B.

RESULTS. During all phases, aortic enhancement was significantly greater in group A than group B (p < 0.01). Hepatic enhancement was significantly greater in group A than group B at 60 and 180 sec (both p < 0.01). There was no significant difference in hepatic enhancement between the two groups at 25 and 40 sec. Tumor-to-liver contrast was significantly greater in group A than group B during the late arterial phase (40 sec, p = 0.02), although there was no significant difference at 25, 60, and 180 sec.

CONCLUSION. Contrast materials with higher iodine concentration are more effective for depicting hypervascular HCCs on MDCT during the late arterial phase.

Introduction

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MDCT yields images with significantly improved time and spatial resolution compared with single-detector CT [1]. MDCT enables the scanning of the whole liver twice during a single breath-hold, and double arterial phase imaging of the liver has been proposed by Murakami et al. [2] and Foley et al. [3].

Technical factors contributing to the depiction of hepatic tumors on contrast-enhanced CT include injection rate, iodine concentration, dose of contrast material, and delay time from start of contrast material injection [4–18]. Several investigators have reported on the effects of injection rate, dose of contrast material, and delay time from the start of contrast material injection. However, the effect of the concentration of iodine in the contrast material on the depiction of hepatic tumors has been less well studied [10, 13]. To our knowledge, there has been no report about the effect of the iodine concentration of the contrast material in hepatic dynamic CT using the double arterial phase scanning technique.

To investigate the effect of iodine content on the depiction of hepatocellular carcinomas (HCCs) on hepatic dynamic CT, we conducted a prospective study comparing two contrast materials with different iodine concentrations in patients with chronic liver disease.

Subjects and Methods

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Patient Population and Study Design
From January 2001 to June 2001, 100 patients suspected of having space-occupying lesions in the liver on the basis of sonography findings or exhibiting elevated levels of a tumor marker (-fetoprotein or protein-induced vitamin K antagonist-II [PIVKA-II]) were assigned to undergo MDCT with one of two contrast injection protocols. A fixed dose of 100 mL of two different iodine concentrations (group A, 370 mg I/mL; group B, 300 mg I/mL) of iopamidol (Iopamiron; Nihon Schering) was administered. The first consecutive 50 patients were assigned to group A, and the subsequent 50 were assigned to group B. Although this study was a prospective one, we did not randomize the iodine concentrations because of the troublesomeness in the procedure of randomization in a busy clinical practice. However, the iodine concentration was changed exactly from the 51st patient to the 100th patient, according to protocol.

The characteristics of the two groups of patients are shown in Table 1. All patients had chronic liver disease due to type B viral hepatitis (n = 15), type C viral hepatitis (n = 83), alcoholic chronic hepatitis (n = 1), or an unknown origin (n = 1). Patients with poor renal function (serum creatine level, > 2.0 mg/dL) or those with a contraindication for iodinated contrast material were excluded from the study. The patients included 72 men and 28 women who ranged in age from 31 to 75 years (median, 64 years). The body weight of the patients ranged from 42 to 102 kg (mean, 59.4 ± 9.6 [SD] kg). There was no significant difference in age or body weight between the two study groups according to the two-tailed Student's t test.

Of the 100 patients, 33 had solitary or multiple HCC nodules and one patient had cholangiocarcinoma. Proof of HCC was obtained by percutaneous liver biopsy (n = 6) or by increased levels of the tumor marker -fetoprotein or PIVKA-II (n = 27). For the latter patients, follow-up CT showed progression of the hepatic tumors. Proof of cholangiocarcinoma was obtained by percutaneous liver biopsy. Of the 33 patients with HCC, 27 had hypervascular tumors and six had hypovascular tumors. We defined hypervascular tumors as those exhibiting an enhancement that was 10 H greater than that of the hepatic parenchyma during the early or late arterial phase, as defined by Awai et al. [10], and hypovascular tumors as those exhibiting an enhancement of 10 H less than that of the hepatic parenchyma of contrast-enhanced scans.

The patients with hypervascular HCCs included 22 men and five women who ranged in age from 43 to 74 years (median, 65 years). The body weight of the patients ranged from 42 to 83 kg (mean, 63.3 ± 6.1 [SD] kg). Of the 27 patients with hypervascular HCC, 15 were in group A and 12 were in group B.

This study was approved by the institutional review board, and written informed consent was obtained from all the patients before the CT examinations.

Contrast Material Infusion and CT Protocol
In both groups, contrast material was administered with a power injector (Autoenhance A-250, Nemoto-kyorindo) using 20-gauge IV catheters inserted into an antecubital vein. Prefilled syringes containing 100 mL of iopamidol were used in both groups. The contrast material was administered at a rate of 3.0 mL/sec, with a monophasic rate of injection in all patients. No saline flush was used after injection of contrast material for both groups.

All patients were scanned on an MDCT scanner (Aquilion Multi, Toshiba Medical Systems) with a 0.5-sec rotation time, 3.0-mm detector-row width, 7.0-mm image thickness and image interval, 5.5 helical pitch, and 30- to 50-cm display field of view at 120 kV and 220–280 mAs. All helical scans were started at the top of the liver and progressed in a cephalocaudal direction, and unenhanced and four-phase contrast-enhanced helical scans of the whole liver were obtained. The contrast-enhanced helical scans of the whole liver began at 25, 40, 60, and 180 sec after the start of contrast material injection. The scanning time for each phase was approximately 6 sec. The scans of the first and second phases were obtained during a single breath-hold. The patients were instructed to hold their breath with tidal inspiration during scanning.

Data Analysis

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The mean attenuation values were measured for the hepatic parenchyma, abdominal aorta, and main portal vein in all 100 patients using a circular region-of-interest (ROI) cursor in the unenhanced scans and four phases of the contrast-enhanced scans in both protocols.

In the liver, attenuation values were measured in at least three separate areas on the image at the level of the porta hepatis and all measured attenuation values were averaged in each phase. An attempt was made to maintain a constant ROI area of approximately 2 cm². Visible blood vessels, bile ducts, and artifacts were carefully excluded from the ROI measurements in the hepatic parenchyma. The contrast enhancement of the liver during each phase was calculated as the absolute difference in the attenuation value of the liver in Hounsfield units between the unenhanced scan and each phase of the contrast-enhanced scan.

In the aorta, attenuation values were measured on the image at the level of the porta hepatis, lower hepatic angle, and top of the diaphragm. All measured attenuation values were averaged in each phase. An attempt was made to maintain a constant ROI area of approximately 1 cm². The contrast enhancement in the aorta during each phase was calculated in the same way as for the hepatic parenchyma.

In the portal vein, attenuation values were measured on the image at the level of the porta hepatis. An attempt was made to maintain a constant ROI area of approximately 1 cm². The contrast enhancement in the main portal vein during each phase was calculated in the same way as for the hepatic parenchyma.

Tumor-to-liver contrast was measured as an indicator of the conspicuity of hepatic tumors. Tumor-to-liver contrast was defined as the difference in attenuation between the hepatic tumor and the surrounding hepatic parenchyma [12]. Tumor-to-liver contrast was measured on contrast-enhanced scans from each phase in the 27 patients with hypervascular HCCs. Tumor attenuation was measured in the most visually enhanced portion of the tumors. An attempt was made to maintain an ROI area of approximately 1 cm². The attenuation values of the hepatic parenchyma used to calculate the tumor-to-liver contrast were measured in three portions of the normal hepatic parenchyma adjacent to the tumor. An attempt was made to maintain a constant ROI area of approximately 2 cm² for hepatic parenchyma.

In the patients with fewer than four tumors, the tumor-to-liver contrast was measured in all the tumors and the average of those values was calculated. In the patients with four or more tumors, the tumor-to-liver contrast was measured in the largest three tumors and averaged. Tumor size ranged from 9 to 68 mm. The attenuation values of the aorta, hepatic parenchyma, main portal vein, and hypervascular HCCs were measured by a radiologist who was unaware of the injection protocol. The quantitative results for enhancement values of the aorta, liver, and main portal vein and the tumor-to-liver contrast values were compared using the two-tailed Student's t test. A p value of less than 0.05 was considered to indicate a statistically significant difference.

Results

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Figure 1A and Table 2 show values of aortic enhancement at 25, 40, 60, and 180 sec after the start of contrast material injection in groups A and B. During all phases, the value of aortic enhancement was significantly higher in group A than group B (p < 0.01).

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —Graphs show time–enhancement curves of abdominal aorta, hepatic parenchyma, and main portal vein after start of contrast material injection in group A (solid line) and group B (dotted line). Bars indicate SEs. Aortic enhancement was significantly greater in group A than group B during all phases.

Similarly, Figure 1B and Table 2 show the change in contrast enhancement of the hepatic parenchyma in groups A and B. At 25 sec, there was no significant difference in values of hepatic enhancement between groups A and B. However, at 40, 60, and 180 sec, the values were significantly higher in group A than group B (p = 0.04, p < 0.01, and p < 0.01, respectively).

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —Graphs show time–enhancement curves of abdominal aorta, hepatic parenchyma, and main portal vein after start of contrast material injection in group A (solid line) and group B (dotted line). Bars indicate SEs. Hepatic enhancement was significantly greater in group A than group B at 40, 60, and 180 sec.

Figure 1C and Table 2 show the change in enhancement of the main portal vein. At 25 and 40 sec, there was no significant difference in the mean values of enhancement of the main portal vein between groups A and B. However, at 60 and 180 sec, the values were significantly higher in group A than group B (p < 0.01, p < 0.01).

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —Graphs show time–enhancement curves of abdominal aorta, hepatic parenchyma, and main portal vein after start of contrast material injection in group A (solid line) and group B (dotted line). Bars indicate SEs. Enhancement of the portal vein was significantly greater in group A than group B at 60 and 180 sec.

Figure 2 and Table 3 show the change of tumor-to-liver contrast values. At 40 sec, the tumor-to-liver contrast values were significantly higher in group A than group B (p = 0.02). At 25, 60, and 180 sec, there was no significant difference in the mean tumor-to-liver contrast values between the groups. Figures 3 and 4 show typical hypervascular HCCs during the late arterial phase for groups A and B. The body weights of the patients were similar to each other, but apparently tumor enhancement was more intense for group A than for group B.

View larger version (12K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2. —Graph shows time–density curves of tumor-to-liver contrast (TLC) values for 27 hypervascular hepatocellular carcinomas in group A (solid line) and group B (dotted line). At 25 sec, there was no significant difference in mean TLC values between groups A and B. At 40 sec, TLC values were significantly higher in group A (p < 0.02). However, there was no significantly difference in mean TLC values between groups A and B at 60 and 180 sec.

View larger version (85K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —54-year-old man with hypervascular HCC in segment VIII. His body weight was 63 kg, and 100 mL of 370 mg I/mL contrast material was administered (group A). CT scan obtained during late arterial phase clearly shows tumor of 24 mm with tumor-to-liver contrast of 69 H.

View larger version (79K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4. —60-year-old woman with hypervascular hepatocellular carcinoma in segment II. Her body weight was 62 kg, and 100 mL of 300 mg I/mL contrast material was administered (group B). CT scan obtained during late arterial phase depicts tumor of 20 mm with tumor-to-liver contrast of 35 H.

Discussion

Top Abstract Introduction Subjects and Methods Data Analysis Results Discussion References

 
In this prospective study, the effect of iodine concentration (370 mg I/mL vs 300 mg I/mL) on the enhancement of the aorta, portal vein, and hepatic parenchyma and the depiction of hypervascular HCCs was evaluated. Although no randomization of iodine concentrations was performed, the iodine concentrations were changed sequentially as part of the protocol. With our protocol, the total volume and injection rate of contrast material were the same in both patient groups. Enhancement of the aorta during both the early and late arterial phases was significantly greater in group A than group B (p < 0.01) (Fig. 1A and Table 2).

In the present study, the injection rate and total volume of the contrast material were constant at 3.0 mL/sec and 100 mL for both groups, respectively, with different iodine concentrations. Thus, the total iodine content for group A was approximately 1.23-fold that for group B. As a result, the injection rate of iodine in group A is considered to be 1.23 fold that in group B. Murakami et al. [2] reported that enhancement of the aorta was improved as the rate of injection of contrast material increased, and our results are comparable with theirs.

There was no significant difference in enhancement of the portal vein and the hepatic parenchyma between the two groups during the early and late arterial phases (Fig. 1A, 1B, 1C and Table 2). Contrast material flows into the portal vein via the superior mesenteric artery and superior mesenteric vein. The use of a higher concentration of contrast material may not shorten the circulation time from the superior mesenteric artery to the portal vein. Therefore, a significant difference was not observed between the two groups in enhancement of the portal vein and hepatic parenchyma during the early and late arterial phases.

From the enhancement pattern for the aorta and hepatic parenchyma, it might be presumed that the tumor-to-liver contrast was greater in group A than group B during both the early and late arterial phases. In fact, this was the case during the late arterial phase (p = 0.02), but not the early arterial phase. The lack of a significant difference in the tumor-to-liver contrast during the early arterial phase may be explained by the fact that the absolute amount of contrast material reaching the hepatic tumors was small in both groups. On the other hand, during the late arterial phase, the iodine dose that flowed into the tumor via the hepatic artery in group A was estimated to be approximately 1.23-fold that in group B. Because the liver receives only 25% of its blood supply from the hepatic artery [19], the difference in iodine that flows into the liver may be minimized between the two groups during the early arterial phase.

In our study, the mean attenuation of the liver during the portal phase in group A and group B was 47.0 H and 38.1 H, respectively, and hepatic enhancement in the portal venous phase was significantly greater in group A (p < 0.001). Heiken et al. [20] reported that a magnitude of hepatic peak enhancement of at least 50 H is desirable to obtain good hepatic images. Accordingly, we concluded that sufficient enhancement could not be obtained in group B. The iodine dose required to achieve a hepatic enhancement of 50 H has been reported to be 521 mg I/kg [20]. For a 60-kg patient, 85 mL of 370 mg I/mL contrast material or 105 mL of 300 mg I/mL contrast material is necessary to administer an iodine concentration of 521 mg I/kg.

Because prefilled syringes were used in the present study and the volume of the contrast material was fixed at 100 mL, theoretically the iodine dose would be insufficient if body weight exceeds 71 kg for group A patients and 59 kg for those in group B. Given that the mean body weight of the patients in our study was 59.4 ± 9.6 kg, the iodine dose was considered insufficient for half of the patients—those in group B. In several countries including Japan, a 100-mL prefilled syringe of contrast material has been widely used for reasons of hygiene and convenience. Under such conditions, it will be useful to administer a contrast material of higher concentration to supply a sufficient iodine dose in patients.

In conclusion, the use of a high-concentration contrast material significantly improved tumor-to-liver contrast during the late arterial phase and enhancement of hepatic parenchyma during the portal venous phase. Administration of a high concentration, 370 mg I/mL, of contrast material is useful in hepatic dynamic CT.

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